Non-Hodgkin's Lymphoma (NHL) is now the fifth most common cancer in the United States. Mantle cell lymphoma (MCL) is an important type of NHL because it has a very poor prognosis with an overall survival of only 3-4 years. MCL is unique in that the cells have a t(11;14)(q13;q32)translocation that results in over-expression of cyclin-D1, an important component of the phosphotidyl inositol 3 Kinase (PI3K) pathway. This pathway is important in mediating cell motility and in enhancing cell survival. PI3K activity results in activation of the mammalian target of rapamycin (mTOR) a key cellular regulator of cell survival. Since MCL cells over-express cyclin-D1, we hypothesized that inhibitors of the PI3K pathway would have anti-tumor activity in MCL. Indeed, we demonstrated that CCI-779, a novel mTOR inhibitor, produced tumor responses in 38% of relapsed MCL patients. This provides important clinical evidence that targeting the PI3K pathway at the level of mTOR can be effective. However, the pathway is complex and it is apparent that targeting other levels of the PI3K. pathway may improve the tumor response. Rituximab is a monoclonal antibody that targets CD20 on MCL cells and produces single agent tumor responses in about 30% of patients. Rituximab inhibits cell signaling pathways at different levels than CCI-779. We hypothesize that the addition of CCI-779 will enhance the anti-tumor activity of rituximab. We propose to study this combination in a phase II study (N038H) along with carefully designed translational research studies that utilize tissue from these patients to investigate the effects of the combination on PI3K pathway proteins. This work is organized into 3 specific aims: Aim 1, to determine the safety and efficacy of the combination of CCI-779 with rituximab in patients with relapsed MCL. Aim 2, to investigate the effect of the combination of rituximab and CCI-779 on PI3K pathway proteins and relate the changes to responses observed in the patients. Aim 3, to study the effect of inhibition of the PI3K pathway on migration of MCL cells. This unique clinical trial has a high likelihood of improving tumor responses in MCL patients and the proposed translational research will improve our understanding of the pathogenesis of this disease and aid in the design of future clinical treatment trials.